title: Ectopic expression of activated notch or SOX2 reveals similar and unique roles in the development of the sensory cell progenitors in the mammalian inner ear.
abstract: Hearing impairment or vestibular dysfunction in humans often results from a permanent loss of critical cell types in the sensory regions of the inner ear, including hair cells, supporting cells, or cochleovestibular neurons. These important cell types arise from a common sensory or neurosensory progenitor, although little is known about how these progenitors are specified. Studies have shown that Notch signaling and the transcription factor Sox2 are required for the development of these lineages. Previously we and others demonstrated that ectopic activation of Notch can direct nonsensory cells to adopt a sensory fate, indicating a role for Notch in early specification events. Here, we explore the relationship between Notch and SOX2 by ectopically activating these factors in nonsensory regions of the mouse cochlea, and demonstrate that, similar to Notch, SOX2 can specify sensory progenitors, consistent with a role downstream of Notch signaling. However, we also show that Notch has a unique role in promoting the proliferation of the sensory progenitors. We further demonstrate that Notch can only induce ectopic sensory regions within a certain time window of development, and that the ectopic hair cells display specialized stereocilia bundles similar to endogenous hair cells. These results demonstrate that Notch and SOX2 can both drive the sensory program in nonsensory cells, indicating these factors may be useful in cell replacement strategies in the inner ear.
authors.affiliation: Department of Ophthalmology and Department of Biomedical Genetics, University of Rochester, Rochester, New York 14642, Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, 3000 CA Rotterdam, the Netherlands, and Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: Wei
authors.initials: W
authors.lastname: Pan
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: Rottier
authors.forename: Karen P
authors.initials: KP
authors.lastname: Steel
authors.forename: Amy E
authors.initials: AE
authors.lastname: Kiernan
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D007758:Ear, Inner / Q000166:cytology* / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051880:Receptors, Notch; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse